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Warren AJ, Liu L, O'Toole DP, Laffey JG, Masterson CH. The impact of the inflammatory pulmonary microenvironment on the behavior and function of mesenchymal stromal cells. Expert Rev Respir Med 2025:1-12. [PMID: 40223328 DOI: 10.1080/17476348.2025.2491715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 03/28/2025] [Accepted: 04/07/2025] [Indexed: 04/15/2025]
Abstract
INTRODUCTION Acute respiratory distress syndrome is characterized by the dysregulation and activation of several inflammatory pathways which lead to widespread inflammation in the lungs. Presently, direct therapy is unavailable and the use of mesenchymal stromal cells as a direct therapy has been proposed, as early-phase studies have shown promise. AREAS COVERED MSCs exert various therapeutic effects on the inflammatory microenvironment, such as anti-microbial effects, restoration of the alveolar-capillary barrier, and exuding various anti-inflammatory effects. However, to exert these effects MSCs need to be submitted to specific external stimuli which can affect their immunomodulation, survival, migration and metabolic state. This review references several articles found through targeted searches in PubMed [Accessed between November 2024 and March 2025], for key terms such as 'mesenchymal stromal cells', 'inflammatory microenvironment', anti-inflammatory', 'metabolism', and 'immunomodulation'. EXPERT OPINION The advancement of MSCs therapy in the treatment of ARDS has not progressed as effectively as one might have anticipated. Several clinical findings have established patient subgroups based on inflammatory cytokine profiles and severity of ARDS. This variation in patients may influence the clinical efficacy of MSCs and instead of concluding that MSCs therapy is not worth pursuing, more research is needed to develop an appropriate therapy.
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Affiliation(s)
- Abigail Jm Warren
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Lanzhi Liu
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Daniel P O'Toole
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - John G Laffey
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland
| | - Claire H Masterson
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
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Jin D, Tu X, Xu W, Zheng H, Zeng J, Bi P, Yang R, Li Y, Ni J, Zhu C, Chen H, Yu D, Wan F. Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy. Int Immunopharmacol 2024; 143:113236. [PMID: 39378654 DOI: 10.1016/j.intimp.2024.113236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/05/2024] [Accepted: 09/19/2024] [Indexed: 10/10/2024]
Abstract
INTRODUCTION Immunogenic cell death (ICD) is a unique cell death triggered by chemotherapy. However, studies elucidating the potential therapeutic role of ICD and the underlying mechanism in diabetic nephropathy (DN) are limited. METHODS WGCNA was conducted on the human kidney biopsy data linked to DN, analyzing gene sets associated with ICD. Gene Set Enrichment Analysis and Gene Set Variation Analysis were utilized to examine the discrepancy in biological function. We used Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and the GeneMANIA database to investigate the function of the signature genes. An analysis using the receiver operating characteristic (ROC) was conducted to validate the diagnostic value of hub genes. Additionally, immune infiltration-related analyses were also performed. In conclusion, we examined the association between the glomerular filtration rate, serum creatinine, and hub genes. Hub genes were validated by immunohistochemistry using db/db mice kidneys. RESULTS WGCNA revealed that the targets in the turquoise unit (1674 genes) exhibited the highest positive correlation with ICD. Furthermore, 4222 statistically significant DEGs were identified when comparing the DN and healthy control groups. Significantly, the KEGG pathway enrichment analysis indicated a connection between ICD and the nuclear factor-kappa B signaling pathway and the synthesis of cytokines (tumor necrosis factor superfamily). ROC analysis revealed that 16 hub genes exhibited strong discriminatory potential as biomarkers for DN. Therefore, immunohistochemical validation, with the potential involvement of chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247) may be crucial for the diagnosis and therapy of DN. CONCLUSIONS DKK3, NR4A1, NR4A2, VEGFA, and DUSP1 may be associated with the development of DN. The pathogenesis of DN may specifically involve chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247), with LCP2 playing a significant role.
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Affiliation(s)
- De Jin
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Xiao Tu
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Wanyue Xu
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Honghui Zheng
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Jiali Zeng
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Peng Bi
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Ruchun Yang
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Yayu Li
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Jun Ni
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China
| | - Caifeng Zhu
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China.
| | - Hongyu Chen
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China.
| | - Dongrong Yu
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China.
| | - Feng Wan
- Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou 310007, Zhejiang, China.
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Starska-Kowarska K. Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies. Cells 2024; 13:1270. [PMID: 39120301 PMCID: PMC11311692 DOI: 10.3390/cells13151270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/11/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
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Affiliation(s)
- Katarzyna Starska-Kowarska
- Department of Physiology, Pathophysiology and Clinical Immunology, Department of Clinical Physiology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; ; Tel.: +48-42-2725237
- Department of Otorhinolaryngology, EnelMed Center Expert, Lodz, Drewnowska 58, 91-001 Lodz, Poland
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Liang Y, Ozdogan E, Hansen MJ, Tang H, Saadiq I, Jordan KL, Krier JD, Gandhi DB, Grande JP, Lerman LO, Taner T. Human liver derived mesenchymal stromal cells ameliorate murine ischemia-induced inflammation through macrophage polarization. Front Immunol 2024; 15:1448092. [PMID: 39104523 PMCID: PMC11298378 DOI: 10.3389/fimmu.2024.1448092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 07/04/2024] [Indexed: 08/07/2024] Open
Abstract
Introduction The immunomodulatory properties of mesenchymal stromal cells (MSC) have been well-characterized in in-vitro and in-vivo models. We have previously shown that liver MSC (L-MSC) are superior inhibitors of T-cell activation/proliferation, NK cell cytolytic function, and macrophage activation compared to adipose (A-MSC) and bone marrow MSC (BM-MSC) in-vitro. Method To test these observations in-vivo, we infused these types of MSC into mice with unilateral renal artery stenosis (RAS), an established model of kidney inflammation. Unilateral RAS was induced via laparotomy in 11-week-old, male 129-S1 mice under general anesthesia. Control mice had sham operations. Human L-MSC, AMSC, and BM-MSC (5x105 cells each) or PBS vehicle were injected intra-arterially 2 weeks after surgery. Kidney morphology was studied 2 weeks after infusion using micro-MRI imaging. Renal inflammation, apoptosis, fibrosis, and MSC retention were studied ex-vivo utilizing western blot, immunofluorescence, and immunohistological analyses. Results The stenotic kidney volume was smaller in all RAS mice, confirming significant injury, and was improved by infusion of all MSC types. All MSC-infused groups had lower levels of plasma renin and proteinuria compared to untreated RAS. Serum creatinine improved in micetreated with BM- and L-MSC. All types of MSC located to and were retained within the stenotic kidneys, but L-MSC retention was significantly higher than A- and BM-MSC. While all groups of MSC-treated mice displayed reduced overall inflammation and macrophage counts, L-MSC showed superior potency in-vivo at localizing to the site of inflammation and inducing M2 (reparative) macrophage polarization to reduce inflammatory changes. Discussion These in-vivo findings extend our in-vitro studies and suggest that L-MSC possess unique anti-inflammatory properties that may play a role in liver-induced tolerance and lend further support to their use as therapeutic agents for diseases with underlying inflammatory pathophysiology.
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Affiliation(s)
- Yun Liang
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Elif Ozdogan
- Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
| | | | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Ishran Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Kyra L. Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - James D. Krier
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Deep B. Gandhi
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Joseph P. Grande
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Timucin Taner
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
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Xu C, Fang X, Lu B, Song Y, Shu W, Lu Z, Su R, Xiang Z, Xu X, Wei X. Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ. Cell Biochem Funct 2024; 42:e4040. [PMID: 38850132 DOI: 10.1002/cbf.4040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/12/2024] [Accepted: 05/07/2024] [Indexed: 06/10/2024]
Abstract
Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.
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Affiliation(s)
- Chenhao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Xixi Fang
- Hangzhou Normal University, Hangzhou, China
| | - Bei Lu
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yisu Song
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Wenzhi Shu
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Zhengyang Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Renyi Su
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
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Szűcs D, Monostori T, Miklós V, Páhi ZG, Póliska S, Kemény L, Veréb Z. Licensing effects of inflammatory factors and TLR ligands on the regenerative capacity of adipose-derived mesenchymal stem cells. Front Cell Dev Biol 2024; 12:1367242. [PMID: 38606318 PMCID: PMC11007080 DOI: 10.3389/fcell.2024.1367242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/15/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction: Adipose tissue-derived mesenchymal stem cells are promising contributors to regenerative medicine, exhibiting the ability to regenerate tissues and modulate the immune system, which is particularly beneficial for addressing chronic inflammatory ulcers and wounds. Despite their inherent capabilities, research suggests that pretreatment amplifies therapeutic effectiveness. Methods: Our experimental design exposed adipose-derived mesenchymal stem cells to six inflammatory factors for 24 h. We subsequently evaluated gene expression and proteome profile alterations and observed the wound closure rate post-treatment. Results: Specific pretreatments, such as IL-1β, notably demonstrated an accelerated wound-healing process. Analysis of gene and protein expression profiles revealed alterations in pathways associated with tissue regeneration. Discussion: This suggests that licensed cells exhibit potentially higher therapeutic efficiency than untreated cells, shedding light on optimizing regenerative strategies using adipose tissue-derived stem cells.
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Affiliation(s)
- Diána Szűcs
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | - Tamás Monostori
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | | | - Zoltán G. Páhi
- Genome Integrity and DNA Repair Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), University of Szeged, Szeged, Hungary
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine-USz Skin Research Group, University of Szeged, Szeged, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Biobank, University of Szeged, Szeged, Hungary
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Mao XF, Zhang XQ, Yao ZY, Mao HJ. Advances in mesenchymal stem cells therapy for tendinopathies. Chin J Traumatol 2024; 27:11-17. [PMID: 38052701 PMCID: PMC10859297 DOI: 10.1016/j.cjtee.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 10/13/2023] [Accepted: 11/07/2023] [Indexed: 12/07/2023] Open
Abstract
Tendinopathies are chronic diseases of an unknown etiology and associated with inflammation. Mesenchymal stem cells (MSCs) have emerged as a viable therapeutic option to combat the pathological progression of tendinopathies, not only because of their potential for multidirectional differentiation and self-renewal, but also their excellent immunomodulatory properties. The immunomodulatory effects of MSCs are increasingly being recognized as playing a crucial role in the treatment of tendinopathies, with MSCs being pivotal in regulating the inflammatory microenvironment by modulating the immune response, ultimately contributing to improved tissue repair. This review will discuss the current knowledge regarding the application of MSCs in tendinopathy treatments through the modulation of the immune response.
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Affiliation(s)
- Xu-Feng Mao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Xi-Qian Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Zhe-Yu Yao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Hai-Jiao Mao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China.
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Mahajan A, Bhattacharyya S. Immunomodulation by mesenchymal stem cells during osteogenic differentiation: Clinical implications during bone regeneration. Mol Immunol 2023; 164:143-152. [PMID: 38011783 DOI: 10.1016/j.molimm.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 11/29/2023]
Abstract
Critical bone defects resulting in delayed and non-union are a major concern in the field of orthopedics. Over the past decade, mesenchymal stem cells (MSCs) have become a promising frontier for bone repair and regeneration owing to their high expansion rate and osteogenic differentiation potential ex vivo. MSCs have also long been associated with their ability to modulate immune response in the recipients. These can even skew the immune response towards pro-inflammatory or anti-inflammatory type by sensing their local microenvironment. MSCs adopt anti-inflammatory phenotype at bone injury site and secrete various immunomodulatory factors such as IDO, NO, TGFβ1 and PGE-2 which have redundant role in osteoblast differentiation and bone formation. As such, several studies have also sought to decipher the immunomodulatory effects of osteogenically differentiated MSCs. The present review discusses the immunomodulatory status of MSCs during their osteogenic differentiation and summarizes few mechanisms that cause immunosuppression by osteogenically differentiated MSCs and its implication during bone healing.
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Affiliation(s)
- Aditi Mahajan
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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Zhong X, Chen J, Wen B, Wu X, Li M, Du F, Chen Y, Deng S, Zhao Y, Shen J, Xiao Z. Potential role of mesenchymal stem cells in T cell aging. J Mol Med (Berl) 2023; 101:1365-1378. [PMID: 37750918 DOI: 10.1007/s00109-023-02371-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 08/21/2023] [Accepted: 09/04/2023] [Indexed: 09/27/2023]
Abstract
Immunosenescence occurs with progressive age. T cell aging is manifested by immunodeficiency and inflammation. The main mechanisms are thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, loss of protein stability, reduction of T cell receptor (TCR) repertoire, naïve-memory T cell ratio imbalance, T cell senescence, and lack of effector plasticity. Mesenchymal stem cells (MSCs) are thought to hold great potential as anti-aging therapy. However, the role of MCSs in T cell aging remains elusive. This review makes a tentative summary of the potential role of MSCs in the protection against T cell aging. It might provide a new idea to intervene in the aging of the immune system.
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Affiliation(s)
- Xianmei Zhong
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- Department of Pharmacy, People's Hospital of Nanbu County, Nanchong, 637300, China
| | - Jie Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
| | - Bo Wen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, No. 1, Section 1, Xianglin Road, Longmatan District, Luzhou, 646000, Sichuan, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, Sichuan, China.
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, Sichuan, China.
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10
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Cabaña-Muñoz ME, Pelaz Fernández MJ, Parmigiani-Cabaña JM, Parmigiani-Izquierdo JM, Merino JJ. Adult Mesenchymal Stem Cells from Oral Cavity and Surrounding Areas: Types and Biomedical Applications. Pharmaceutics 2023; 15:2109. [PMID: 37631323 PMCID: PMC10459416 DOI: 10.3390/pharmaceutics15082109] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 07/28/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Adult mesenchymal stem cells are those obtained from the conformation of dental structures (DMSC), such as deciduous and permanent teeth and other surrounding tissues. Background: The self-renewal and differentiation capacities of these adult stem cells allow for great clinical potential. Because DMSC are cells of ectomesenchymal origin, they reveal a high capacity for complete regeneration of dental pulp, periodontal tissue, and other biomedical applications; their differentiation into other types of cells promotes repair in muscle tissue, cardiac, pancreatic, nervous, bone, cartilage, skin, and corneal tissues, among others, with a high predictability of success. Therefore, stem and progenitor cells, with their exosomes of dental origin and surrounding areas in the oral cavity due to their plasticity, are considered a fundamental pillar in medicine and regenerative dentistry. Tissue engineering (MSCs, scaffolds, and bioactive molecules) sustains and induces its multipotent and immunomodulatory effects. It is of vital importance to guarantee the safety and efficacy of the procedures designed for patients, and for this purpose, more clinical trials are needed to increase the efficacy of several pathologies. Conclusion: From a bioethical and transcendental anthropological point of view, the human person as a unique being facilitates better clinical and personalized therapy, given the higher prevalence of dental and chronic systemic diseases.
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Affiliation(s)
- María Eugenia Cabaña-Muñoz
- CIROM—Centro de Rehabilitación Oral Multidisciplinaria, 30001 Murcia, Spain; (M.E.C.-M.); (J.M.P.-C.); (J.M.P.-I.)
| | | | - José María Parmigiani-Cabaña
- CIROM—Centro de Rehabilitación Oral Multidisciplinaria, 30001 Murcia, Spain; (M.E.C.-M.); (J.M.P.-C.); (J.M.P.-I.)
| | | | - José Joaquín Merino
- Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M), 28040 Madrid, Spain
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11
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Szűcs D, Miklós V, Monostori T, Guba M, Kun-Varga A, Póliska S, Kis E, Bende B, Kemény L, Veréb Z. Effect of Inflammatory Microenvironment on the Regenerative Capacity of Adipose-Derived Mesenchymal Stem Cells. Cells 2023; 12:1966. [PMID: 37566046 PMCID: PMC10416993 DOI: 10.3390/cells12151966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/12/2023] [Accepted: 07/22/2023] [Indexed: 08/12/2023] Open
Abstract
Adipose-derived mesenchymal stem cells are increasingly being used in regenerative medicine as cell therapy targets, including in the treatment of burns and ulcers. The regenerative potential of AD-MSCs and some of their immunological properties are known from in vitro studies; however, in clinical applications, cells are used in non-ideal conditions and can behave differently in inflammatory environments, affecting the efficacy and outcome of therapy. Our aim was to investigate and map the pathways that the inflammatory microenvironment can induce in these cells. High-throughput gene expression assays were performed on AD-MSCs activated with LPS and TNFα. Analysis of RNA-Seq data showed that control, LPS-treated and TNFα-treated samples exhibited distinct gene expression patterns. LPS treatment increased the expression of 926 genes and decreased the expression of 770 genes involved in cell division, DNA repair, the cell cycle, and several metabolic processes. TNFα treatment increased the expression of 174 genes and decreased the expression of 383 genes, which are related to cell division, the immune response, cell proliferation, and differentiation. We also map the biological pathways by further investigating the most altered genes using the Gene Ontology and KEGG databases. Secreted cytokines, which are important in the immunological response, were also examined at the protein level, and a functional assay was performed to assess wound healing. Activated AD-MSC increased the secretion of IL-6, IL-8 and CXCL-10, and also the closure of wounds. AD-MSCs presented accelerated wound healing under inflammation conditions, suggesting that we could use this cell in clinical application.
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Affiliation(s)
- Diána Szűcs
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Doctoral School of Clinical Medicine, University of Szeged, 6720 Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Vanda Miklós
- Biobank, University of Szeged, 6720 Szeged, Hungary;
| | - Tamás Monostori
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Melinda Guba
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Anikó Kun-Varga
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary;
| | - Erika Kis
- Dermatosurgery and Plastic Surgery, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (E.K.); (B.B.)
| | - Balázs Bende
- Dermatosurgery and Plastic Surgery, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (E.K.); (B.B.)
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine-USz Skin Research Group, University of Szeged, 6720 Szeged, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
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12
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Zhang W, Ling Y, Sun Y, Xiao F, Wang L. Extracellular Vesicles Derived from Mesenchymal Stem Cells Promote Wound Healing and Skin Regeneration by Modulating Multiple Cellular Changes: A Brief Review. Genes (Basel) 2023; 14:1516. [PMID: 37628568 PMCID: PMC10453884 DOI: 10.3390/genes14081516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are biologically active substances secreted by MSCs into the extracellular matrix that play an immunomodulatory role in skin damage repair. To investigate the mechanism of MSC-EVs in reducing inflammation, promoting angiogenesis, promoting the proliferation and migration of epithelial cells and fibroblasts, and extracellular matrix remodeling during wound healing, we focused on the effects of EVs on multiple cell types at various stages of skin injury. A literature review was conducted to explore related research on the influence of MSC-EVs on the types of cells involved in wound healing. MSC-EVs show a strong regulatory ability on immune cells involved in the regulation of inflammation, including macrophages, neutrophils, and T cells, and other cells involved in tissue proliferation and remodeling, such as fibroblasts, keratinocytes, and endothelial cells, during wound healing in in vitro and in vivo experiments, which substantially promoted the understanding of wound healing in the field of trauma medicine. MSC-EVs have potential applications in combating poor skin wound healing. Elucidating the mechanism of action of EVs in the wound-healing process would greatly advance the understanding of therapeutic wound healing.
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Affiliation(s)
- Weiyuan Zhang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao 266000, China; (W.Z.); (Y.L.); (Y.S.)
| | - Yang Ling
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao 266000, China; (W.Z.); (Y.L.); (Y.S.)
| | - Yang Sun
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao 266000, China; (W.Z.); (Y.L.); (Y.S.)
| | - Fengjun Xiao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lisheng Wang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao 266000, China; (W.Z.); (Y.L.); (Y.S.)
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13
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Soni SS, D'Elia AM, Rodell CB. Control of the post-infarct immune microenvironment through biotherapeutic and biomaterial-based approaches. Drug Deliv Transl Res 2023; 13:1983-2014. [PMID: 36763330 PMCID: PMC9913034 DOI: 10.1007/s13346-023-01290-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2023] [Indexed: 02/11/2023]
Abstract
Ischemic heart failure (IHF) is a leading cause of morbidity and mortality worldwide, for which heart transplantation remains the only definitive treatment. IHF manifests from myocardial infarction (MI) that initiates tissue remodeling processes, mediated by mechanical changes in the tissue (loss of contractility, softening of the myocardium) that are interdependent with cellular mechanisms (cardiomyocyte death, inflammatory response). The early remodeling phase is characterized by robust inflammation that is necessary for tissue debridement and the initiation of repair processes. While later transition toward an immunoregenerative function is desirable, functional reorientation from an inflammatory to reparatory environment is often lacking, trapping the heart in a chronically inflamed state that perpetuates cardiomyocyte death, ventricular dilatation, excess fibrosis, and progressive IHF. Therapies can redirect the immune microenvironment, including biotherapeutic and biomaterial-based approaches. In this review, we outline these existing approaches, with a particular focus on the immunomodulatory effects of therapeutics (small molecule drugs, biomolecules, and cell or cell-derived products). Cardioprotective strategies, often focusing on immunosuppression, have shown promise in pre-clinical and clinical trials. However, immunoregenerative therapies are emerging that often benefit from exacerbating early inflammation. Biomaterials can be used to enhance these therapies as a result of their intrinsic immunomodulatory properties, parallel mechanisms of action (e.g., mechanical restraint), or by enabling cell or tissue-targeted delivery. We further discuss translatability and the continued progress of technologies and procedures that contribute to the bench-to-bedside development of these critically needed treatments.
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Affiliation(s)
- Shreya S Soni
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Arielle M D'Elia
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Christopher B Rodell
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA.
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14
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Behm C, Blufstein A, Gahn J, Moritz A, Rausch-Fan X, Andrukhov O. 25-hydroxyvitamin D 3 generates immunomodulatory plasticity in human periodontal ligament-derived mesenchymal stromal cells that is inflammatory context-dependent. Front Immunol 2023; 14:1100041. [PMID: 36761739 PMCID: PMC9902380 DOI: 10.3389/fimmu.2023.1100041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
INTRODUCTION Human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) exhibit a tight bi-directional interaction with CD4+ T lymphocytes. The hPDL-MSCs' immunomodulatory abilities are drastically enhanced by pro-inflammatory cytokines via boosting the expression of various immunomediators. 25-hydroxyvitamin D3 (25(OH)D3), the major metabolite of vitamin D3 in the blood, affects both hPDL-MSCs and CD4+ T lymphocytes, but its influence on their interaction is unknown. METHODS Therefore, primary hPDL-MSCs were stimulated in vitro with tumor necrosis factor (TNF)-α a or interleukin (IL)-1β in the absence and presence of 25(OH)D3 followed by an indirect co-culture with phytohemagglutinin-activated CD4+ T lymphocytes. The CD4+ T lymphocyte proliferation, viability, and cytokine secretion were analyzed. Additionally, the expression of various immunomediators in hPDL-MSCs was investigated, and their implication was verified by using pharmacological inhibitors. RESULTS 25(OH)D3 significantly counteracted the suppressive effects of IL-1β-treated hPDL-MSCs on CD4+ T lymphocyte proliferation, whereas no effects were observed in the presence of TNF-α. Additionally, 25(OH)D3 significantly increased the percentage of viable CD4+ T lymphocytes via TNF-α- or IL-1β-treated hPDL-MSCs. It also caused a significant decrease in interferon-γ, IL-17A, and transforming growth factor-β productions, which were triggered by TNF-α-treated hPDL-MSCs. 25(OH)D3 significantly decreased the production of various immunomediators in hPDL-MSCs. Inhibition of two of them, prostaglandin E2 and indoleamine-2,3-dioxygenase-1, partially abolished some of the hPDL-MSCs-mediated effects of 25(OH)D3 on CD4+ T lymphocytes. CONCLUSION These data indicate that 25(OH)D3 influences the immunomodulatory activities of hPDL-MSCs. This modulatory potential seems to have high plasticity depending on the local cytokine conditions and may be involved in regulating periodontal tissue inflammatory processes.
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Affiliation(s)
- Christian Behm
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Alice Blufstein
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Johannes Gahn
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Andreas Moritz
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Xiaohui Rausch-Fan
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
- Center for Clinical Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Oleh Andrukhov
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
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15
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Mesenchymal Stem Cells in Radiation-Induced Pulmonary Fibrosis: Future Prospects. Cells 2022; 12:cells12010006. [PMID: 36611801 PMCID: PMC9818136 DOI: 10.3390/cells12010006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Radiation-induced pulmonary fibrosis (RIPF) is a general and fatal side effect of radiotherapy, while the pathogenesis has not been entirely understood yet. By now, there is still no effective clinical intervention available for treatment of RIPF. Recent studies revealed mesenchymal stromal cells (MSCs) as a promising therapy treatment due to their homing and differentiation ability, paracrine effects, immunomodulatory effects, and MSCs-derived exosomes. Nevertheless, problems and challenges in applying MSCs still need to be taken seriously. Herein, we reviewed the mechanisms and challenges in the applications of MSCs in treating RIPF.
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16
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Arabiyat AS, Yeisley DJ, Güiza-Argüello VR, Qureshi F, Culibrk RA, Hahn J, Hahn MS. Effects of Stromal Cell Conditioned Medium and Antipurinergic Treatment on Macrophage Phenotype. Tissue Eng Part C Methods 2022; 28:656-671. [PMID: 36329666 PMCID: PMC9807257 DOI: 10.1089/ten.tec.2022.0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
The immunomodulatory capacity of the human mesenchymal stromal cell (MSC) secretome has been a critical driver for the development of cell-free MSC products, such as conditioned medium (CM), for regenerative medicine applications. This is particularly true as cell-free MSC products present several advantages over direct autologous or allogeneic MSC delivery with respect to safety, manufacturability, and defined potency. Recently, significant effort has been placed into creating novel MSC CM formulations with an immunomodulatory capacity tailored for specific regenerative contexts. For instance, the immunoregulatory nature of MSC CM has previously been tuned through a number of cytokine-priming strategies. Herein, we propose an alternate method to tailor the immunomodulatory "phenotype" of cytokine-primed MSC CM through coupling with the pharmacological agent, suramin. Suramin interferes with the signaling of purines including extracellular adenosine triphosphate (ATP), which plays a critical role in the activation of the innate immune system after injury. Toward this end, human THP-1-derived macrophages were activated to a proinflammatory phenotype and treated with (1) unprimed/native MSC CM, (2) interferon-γ/tumor necrosis factor α-primed MSC CM (primed CM), (3) suramin alone, or (4) primed MSC CM and suramin (primed CM/suramin). Markers of key macrophage functions-cytokine secretion, autophagy, oxidative stress modulation, and activation/migration-were assessed. Consistent with previous literature, primed CM elevated macrophage secretion of several proinflammatory and pleiotropic cytokines relative to native CM; whereas addition of suramin imparted consistent shifts in terms of TNFα (↓), interleukin-10 (↓), and hepatocyte growth factor (↑) irrespective of CM. In addition, both primed CM and suramin, individually and combined, increased reactive oxygen species production relative to native CM, and addition of suramin to primed CM shifted levels of CX3CL1, a factor involved in ATP-associated macrophage regulation. Varimax rotation assessment of the secreted cytokine profiles confirmed that primed CM/suramin resulted in a THP-1 phenotypic shift away from the lipopolysaccharide-activated proinflammatory state that was distinct from that of primed CM or native CM alone. This altered primed CM/suramin-associated phenotype may prove beneficial for healing in certain regenerative contexts. These results may inform future work coupling antipurinergic treatments with MSC-derived therapies in regenerative medicine applications.
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Affiliation(s)
- Ahmad S. Arabiyat
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
| | - Daniel J. Yeisley
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
| | - Viviana R. Güiza-Argüello
- Department of Metallurgical Engineering and Materials Science, Universidad Industrial de Santander, Bucaramanga, Colombia
| | - Fatir Qureshi
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
| | - Robert A. Culibrk
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
| | - Juergen Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
| | - Mariah S. Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
- Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI), Troy, New York, USA
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17
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Shirbaghaee Z, Hassani M, Heidari Keshel S, Soleimani M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res Ther 2022; 13:462. [PMID: 36068595 PMCID: PMC9449296 DOI: 10.1186/s13287-022-03148-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/25/2022] Open
Abstract
Critical limb ischemia (CLI), the terminal stage of peripheral arterial disease (PAD), is characterized by an extremely high risk of amputation and vascular issues, resulting in severe morbidity and mortality. In patients with severe limb ischemia with no alternative therapy options, such as endovascular angioplasty or bypass surgery, therapeutic angiogenesis utilizing cell-based therapies is vital for increasing blood flow to ischemic regions. Mesenchymal stem cells (MSCs) are currently considered one of the most encouraging cells as a regenerative alternative for the surgical treatment of CLI, including restoring tissue function and repairing ischemic tissue via immunomodulation and angiogenesis. The regenerative treatments for limb ischemia based on MSC therapy are still considered experimental. Despite recent advances in preclinical and clinical research studies, it is not recommended for regular clinical use. In this study, we review the immunomodulatory features of MSC besides the current understanding of different sources of MSC in the angiogenic treatment of CLI subjects and their potential applications as therapeutic agents. Specifically, this paper concentrates on the most current clinical application issues, and several recommendations are provided to improve the efficacy of cell therapy for CLI patients.
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Affiliation(s)
- Zeinab Shirbaghaee
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of Vascular and Endovascular Surgery, Ayatollah Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran.
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18
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Mesenchymal stem cells: A living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185:114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 12/16/2022]
Abstract
The strategy of using mesenchymal stem cells (MSCs) as a living carrier for active delivery of therapeutic agents targeting tumor sites has been attempted in a wide range of studies to validate the feasibility and efficacy for tumor treatment. This approach reveals powerful tumor targeting and tumor penetration. In addition, MSCs have been confirmed to actively participate in immunomodulation of the tumor microenvironment. Thus, MSCs are not inert delivery vehicles but have a strong impact on the fate of tumor cells. In this review, these active properties of MSCs are addressed to highlight the advantages and challenges of using MSCs for tumor-targeted delivery. In addition, some of the latest examples of using MSCs to carry a variety of anti-tumor agents for tumor-targeted therapy are summarized. Recent technologies to improve the performance and safety of this delivery strategy will be introduced. The advances, applications, and challenges summarized in this review will provide a general understanding of this promising strategy for actively delivering drugs to tumor tissues.
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19
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Kuca-Warnawin E, Plebańczyk M, Ciechomska M, Olesińska M, Szczęsny P, Kontny E. Impact of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Rheumatic Disease Patients on T Helper Cell Differentiation. Int J Mol Sci 2022; 23:ijms23105317. [PMID: 35628127 PMCID: PMC9140468 DOI: 10.3390/ijms23105317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
Complex pathogenesis of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is associated with an imbalance of various Th-cell subpopulations. Mesenchymal stem cells (MSCs) have the ability to restore this balance. However, bone marrow-derived MSCs of SLE and SSc patients exhibit many abnormalities, whereas the properties of adipose derived mesenchymal stem cells (ASCS) are much less known. Therefore, we examined the effect of ASCs obtained from SLE (SLE/ASCs) and SSc (SSc/ASCs) patients on Th subset differentiation, using cells from healthy donors (HD/ASCs) as controls. ASCs were co-cultured with activated CD4+ T cells or peripheral blood mononuclear cells. Expression of transcription factors defining Th1, Th2, Th17, and regulatory T cell (Tregs) subsets, i.e., T-bet, GATA3, RORc, and FoxP3, were analysed by quantitative RT-PCR, the concentrations of subset-specific cytokines were measured by ELISA, and Tregs formation by flow cytometry. Compared with HD/ASCs, SLE/ASCs and especially SSc/ASCs triggered Th differentiation which was disturbed at the transcription levels of genes encoding Th1- and Tregs-related transcription factors. However, we failed to find functional consequences of this abnormality, because all tested ASCs similarly switched differentiation from Th1 to Th2 direction with accompanying IFNγ/IL-4 ratio decrease, up-regulated Th17 formation and IL-17 secretion, and up-regulated classical Tregs generation.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
- Correspondence:
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Olesińska
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Piotr Szczęsny
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
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Wang Z, Le H, Wang Y, Liu H, Li Z, Yang X, Wang C, Ding J, Chen X. Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions. Bioact Mater 2022; 11:317-338. [PMID: 34977434 PMCID: PMC8671106 DOI: 10.1016/j.bioactmat.2021.10.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/19/2021] [Accepted: 10/02/2021] [Indexed: 12/12/2022] Open
Abstract
The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (e.g., osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (e.g., osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.
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Affiliation(s)
- Zhonghan Wang
- Department of Plastic and Reconstruct Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, PR China
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - Hanxiang Le
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - Yanbing Wang
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - He Liu
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - Zuhao Li
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - Xiaoyu Yang
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 130041, PR China
| | - Chenyu Wang
- Department of Plastic and Reconstruct Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, PR China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
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21
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Russo V, El Khatib M, Prencipe G, Citeroni MR, Faydaver M, Mauro A, Berardinelli P, Cerveró-Varona A, Haidar-Montes AA, Turriani M, Di Giacinto O, Raspa M, Scavizzi F, Bonaventura F, Stöckl J, Barboni B. Tendon Immune Regeneration: Insights on the Synergetic Role of Stem and Immune Cells during Tendon Regeneration. Cells 2022; 11:434. [PMID: 35159244 PMCID: PMC8834336 DOI: 10.3390/cells11030434] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 12/11/2022] Open
Abstract
Tendon disorders represent a very common pathology in today's population, and tendinopathies that account 30% of tendon-related injuries, affect yearly millions of people which in turn cause huge socioeconomic and health repercussions worldwide. Inflammation plays a prominent role in the development of tendon pathologies, and advances in understanding the underlying mechanisms during the inflammatory state have provided additional insights into its potential role in tendon disorders. Different cell compartments, in combination with secreted immune modulators, have shown to control and modulate the inflammatory response during tendinopathies. Stromal compartment represented by tenocytes has shown to display an important role in orchestrating the inflammatory response during tendon injuries due to the interplay they exhibit with the immune-sensing and infiltrating compartments, which belong to resident and recruited immune cells. The use of stem cells or their derived secretomes within the regenerative medicine field might represent synergic new therapeutical approaches that can be used to tune the reaction of immune cells within the damaged tissues. To this end, promising opportunities are headed to the stimulation of macrophages polarization towards anti-inflammatory phenotype together with the recruitment of stem cells, that possess immunomodulatory properties, able to infiltrate within the damaged tissues and improve tendinopathies resolution. Indeed, the comprehension of the interactions between tenocytes or stem cells with the immune cells might considerably modulate the immune reaction solving hence the inflammatory response and preventing fibrotic tissue formation. The purpose of this review is to compare the roles of distinct cell compartments during tendon homeostasis and injury. Furthermore, the role of immune cells in this field, as well as their interactions with stem cells and tenocytes during tendon regeneration, will be discussed to gain insights into new ways for dealing with tendinopathies.
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Affiliation(s)
- Valentina Russo
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Maria Rita Citeroni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Melisa Faydaver
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Annunziata Mauro
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Paolo Berardinelli
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Arlette A. Haidar-Montes
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Maura Turriani
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
| | - Marcello Raspa
- National Research Council (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), Institute of Biochemistry and Cellular Biology (IBBC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Ferdinando Scavizzi
- National Research Council (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), Institute of Biochemistry and Cellular Biology (IBBC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Fabrizio Bonaventura
- National Research Council (CNR), Campus International Development (EMMA-INFRAFRONTIER-IMPC), Institute of Biochemistry and Cellular Biology (IBBC), 00015 Monterotondo Scalo, Italy; (M.R.); (F.S.); (F.B.)
| | - Johannes Stöckl
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (V.R.); (M.E.K.); (M.R.C.); (M.F.); (A.M.); (P.B.); (A.C.-V.); (A.A.H.-M.); (M.T.); (O.D.G.); (B.B.)
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22
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Overview of signal transduction between LL37 and bone marrow-derived MSCs. J Mol Histol 2022; 53:149-157. [DOI: 10.1007/s10735-021-10048-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/06/2021] [Indexed: 12/27/2022]
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23
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Charrier M, Lorant J, Contreras-Lopez R, Téjédor G, Blanquart C, Lieubeau B, Schleder C, Leroux I, Deshayes S, Fonteneau JF, Babarit C, Hamel A, Magot A, Péréon Y, Viau S, Delorme B, Luz-Crawford P, Lamirault G, Djouad F, Rouger K. Human MuStem cells repress T-cell proliferation and cytotoxicity through both paracrine and contact-dependent pathways. Stem Cell Res Ther 2022; 13:7. [PMID: 35012660 PMCID: PMC8751303 DOI: 10.1186/s13287-021-02681-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 12/09/2021] [Indexed: 11/23/2022] Open
Abstract
Background Muscular dystrophies (MDs) are inherited diseases in which a dysregulation of the immune response exacerbates disease severity and are characterized by infiltration of various immune cell types leading to muscle inflammation, fiber necrosis and fibrosis. Immunosuppressive properties have been attributed to mesenchymal stem cells (MSCs) that regulate the phenotype and function of different immune cells. However, such properties were poorly considered until now for adult stem cells with myogenic potential and advanced as possible therapeutic candidates for MDs. In the present study, we investigated the immunoregulatory potential of human MuStem (hMuStem) cells, for which we previously demonstrated that they can survive in injured muscle and robustly counteract adverse tissue remodeling. Methods The impact of hMuStem cells or their secretome on the proliferative and phenotypic properties of T-cells was explored by co-culture experiments with either peripheral blood mononucleated cells or CD3-sorted T-cells. A comparative study was produced with the bone marrow (BM)-MSCs. The expression profile of immune cell-related markers on hMuStem cells was determined by flow cytometry while their secretory profile was examined by ELISA assays. Finally, the paracrine and cell contact-dependent effects of hMuStem cells on the T-cell-mediated cytotoxic response were analyzed through IFN-γ expression and lysis activity. Results Here, we show that hMuStem cells have an immunosuppressive phenotype and can inhibit the proliferation and the cytotoxic response of T-cells as well as promote the generation of regulatory T-cells through direct contact and via soluble factors. These effects are associated, in part, with the production of mediators including heme-oxygenase-1, leukemia inhibitory factor and intracellular cell adhesion molecule-1, all of which are produced at significantly higher levels by hMuStem cells than BM-MSCs. While the production of prostaglandin E2 is involved in the suppression of T-cell proliferation by both hMuStem cells and BM-MSCs, the participation of inducible nitric oxide synthase activity appears to be specific to hMuStem cell-mediated one. Conclusions Together, our findings demonstrate that hMuStem cells are potent immunoregulatory cells. Combined with their myogenic potential, the attribution of these properties reinforces the positioning of hMuStem cells as candidate therapeutic agents for the treatment of MDs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02681-3.
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Affiliation(s)
- Marine Charrier
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France.,L'institut du Thorax, INSERM, CNRS, UNIV Nantes, 44007, Nantes, France.,Université de Nantes, Nantes, France
| | - Judith Lorant
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France
| | - Rafael Contreras-Lopez
- INSERM U1183 IRMB, Hôpital Saint Eloi, CHRU Montpellier, Université de Montpellier, 80, Rue Augustin Fliche, 34295, Montpellier, France.,Laboratorio de Immunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Las Condes, Chile
| | - Gautier Téjédor
- INSERM U1183 IRMB, Hôpital Saint Eloi, CHRU Montpellier, Université de Montpellier, 80, Rue Augustin Fliche, 34295, Montpellier, France
| | | | | | - Cindy Schleder
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France
| | - Isabelle Leroux
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France
| | - Sophie Deshayes
- CNRS, INSERM, CRCINA, Université de Nantes, 44000, Nantes, France
| | | | - Candice Babarit
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France
| | - Antoine Hamel
- Service de Chirurgie Infantile, Centre Hospitalier Universitaire (CHU) de Nantes, 44093, Nantes, France
| | - Armelle Magot
- Laboratoire d'Explorations Fonctionnelles, Centre de Référence Maladies Neuromusculaires AOC, CHU Nantes, 44093, Nantes, France
| | - Yann Péréon
- Laboratoire d'Explorations Fonctionnelles, Centre de Référence Maladies Neuromusculaires AOC, CHU Nantes, 44093, Nantes, France
| | - Sabrina Viau
- Biotherapy Division, Macopharma, 59420, Mouvaux, France
| | - Bruno Delorme
- Biotherapy Division, Macopharma, 59420, Mouvaux, France
| | - Patricia Luz-Crawford
- Laboratorio de Immunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Las Condes, Chile.,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | | | - Farida Djouad
- INSERM U1183 IRMB, Hôpital Saint Eloi, CHRU Montpellier, Université de Montpellier, 80, Rue Augustin Fliche, 34295, Montpellier, France.
| | - Karl Rouger
- INRAE, Oniris, PAnTher, UMR 703, Oniris - Site de La Chantrerie, 101, Route de Gachet, CS. 40706, 44307, Nantes, France.
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24
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Soni N, Gupta S, Rawat S, Krishnakumar V, Mohanty S, Banerjee A. MicroRNA-Enriched Exosomes from Different Sources of Mesenchymal Stem Cells Can Differentially Modulate Functions of Immune Cells and Neurogenesis. Biomedicines 2021; 10:biomedicines10010069. [PMID: 35052749 PMCID: PMC8772751 DOI: 10.3390/biomedicines10010069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 01/10/2023] Open
Abstract
Adult Mesenchymal stem cells-derived exosomes carry several biologically active molecules that play prominent roles in controlling disease manifestations. The content of these exosomes, their functions, and effect on the immune cells may differ depending on their tissue sources. Therefore, in this study, we purified the exosomes from three different sources and, using the RNA-Seq approach, highly abundant microRNAs were identified and compared between exosomes and parental cells. The effects of exosomes on different immune cells were studied in vitro by incubating exosomes with PBMC and neutrophils and assessing their functions. The expression levels of several miRNAs varied within the different MSCs and exosomes. Additionally, the expression profile of most of the miRNAs was not similar to that of their respective sources. Exosomes isolated from different sources had different abilities to induce the process of neurogenesis and angiogenesis. Moreover, these exosomes demonstrated their varying effect on PBMC proliferation, neutrophil survival, and NET formation, highlighting their versatility and broad interaction with immune cells. The knowledge gained from this study will improve our understanding of the miRNA landscape of exosomes from hMSCs and provide a resource for further improving our understanding of exosome cargo and their interaction with immune cells.
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Affiliation(s)
- Naina Soni
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Suchi Gupta
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Surender Rawat
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Vishnu Krishnakumar
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Sujata Mohanty
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
- Correspondence: (S.M.); (A.B.)
| | - Arup Banerjee
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
- Correspondence: (S.M.); (A.B.)
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25
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Di Paola A, Palumbo G, Tortora C, Argenziano M, Catanoso M, Di Leva C, Ceglie G, Perrotta S, Locatelli F, Rossi F. Eltrombopag in paediatric immune thrombocytopenia: Iron metabolism modulation in mesenchymal stromal cells. Br J Haematol 2021; 197:110-119. [PMID: 34961933 PMCID: PMC9303225 DOI: 10.1111/bjh.18012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 01/13/2023]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease caused by platelet destruction mediated by auto-antibody production. It is characterized by a compromised immune system and alteration of the inflammatory response. Mesenchymal stromal cells (MSCs) play an important role in modulating immune and inflammatory processes, exerting immune-suppressing and anti-inflammatory properties. In ITP-MSCs the activity and survival are strongly impaired. Eltrombopag (ELT) is a thrombopoietin receptor agonist approved in chronic ITP for stimulating platelet production. It has immunomodulating properties by stimulating T and B regulatory cell activity and by promoting a macrophage switch from the pro-inflammatory to the anti-inflammatory phenotype. ELT also exhibits iron-chelating properties. Iron is a crucial element involved in several physiologic processes, but its intracellular accumulation determines cell damages. Therefore, for the first time we analysed the effect of ELT on ITP-MSCs demonstrating its ability to restore survival and activity of MSCs directly and to promote their survival and proliferation indirectly, by iron metabolism modulation.
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Affiliation(s)
- Alessandra Di Paola
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Chiara Tortora
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maura Argenziano
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Caterina Di Leva
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giulia Ceglie
- Department of Haematology, Bambino Gesù Hospital, Rome, Italy
| | - Silverio Perrotta
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Francesca Rossi
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
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26
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Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells Int 2021; 2021:5513309. [PMID: 34824587 PMCID: PMC8610645 DOI: 10.1155/2021/5513309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a severe health problem that endangers human health worldwide. Mesenchymal stem cell (MSC) therapy is a novel treatment for patients with different liver diseases due to its vast expansion potential and distinctive immunomodulatory properties. Despite several preclinical trials having confirmed the considerable efficacy of MSC therapy in liver diseases, the questionable safety and efficacy still limit its application. As a precursor cell, MSCs can adjust their characteristics in response to the surrounding microenvironment. The microenvironment provides physical and chemical factors essential for stem cell survival, proliferation, and differentiation. However, the mechanisms are still not completely understood. We, therefore, summarized the mechanisms underlying the MSC immune response, especially the interaction between MSCs and the liver microenvironment, discussing how to achieve better therapeutic effects.
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27
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Fukushima K, Itaba N, Kono Y, Okazaki S, Enokida S, Kuranobu N, Murakami J, Enokida M, Nagashima H, Kanzaki S, Namba N, Shiota G. Secreted matrix metalloproteinase-14 is a predictor for antifibrotic effect of IC-2-engineered mesenchymal stem cell sheets on liver fibrosis in mice. Regen Ther 2021; 18:292-301. [PMID: 34504910 PMCID: PMC8399086 DOI: 10.1016/j.reth.2021.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/03/2021] [Accepted: 08/11/2021] [Indexed: 12/31/2022] Open
Abstract
Introduction Transplantation of IC-2-engineered bone marrow-derived mesenchymal stem cell (BM-MSC) sheets (IC-2 sheets) was previously reported to potentially reduce liver fibrosis. Methods This study prepared IC-2-engineered cell sheets from multiple lots of BM-MSCs and examined the therapeutic effects of these cell sheets on liver fibrosis induced by carbon tetrachloride in mice. The predictive factors for antifibrotic effect on liver fibrosis were tried to identify in advance. Results Secreted matrix metalloproteinase (MMP)-14 was found to be a useful predictive factor to reduce liver fibrosis. Moreover, the cutoff index of MMP-14 for 30% reduction of liver fibrosis was 0.918 fg/cell, judging from univariate analysis and receiver operating curve analysis. In addition, MMP-13 activity and thioredoxin contents in IC-2 sheets were also inversely correlated with hepatic hydroxyproline contents. Finally, IC-2 was also found to promote MMP-14 secretion from BM-MSCs of elderly patients. Surprisingly, the values of secreted MMP-14 from BM-MSCs of elderly patients were much higher than those of young persons. Conclusion The results of this study suggest that the IC-2 sheets would be applicable to clinical use in autologous transplantation for patients with cirrhosis regardless of the patient's age.
IC-2- sheets from multiple lots of BM-MSCs ameliorate liver fibrosis in mice. Secreted MMP-14 is a useful predictive marker to reduce liver fibrosis. MMP-13 and thioredoxin in IC-2 sheets were also associated with liver fibrosis. IC-2 also promotes MMP-14 secretion from BM-MSCs of elderly patients.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BM-MSCs, bone marrow-derived mesenchymal stem cells
- C3, complement C3
- CCl4, carbon tetrachloride
- DMSO, dimethyl sulfoxide
- EDTA, ethylenediamine tetra-acetic acid
- FACS, Fluorescence-activated cell sorter
- FALD, fontan-associated liver disease
- GAPDH, Glyceraldehyde 3-phosphate dehydrogenase
- HCC, hepatic cellular carcinoma
- HLA, human leukocyte antigen
- HSCs, hepatic stellate cells
- Hepatic cell sheets
- IgG, immunoglobulin G
- LC, liver cirrhosis
- MMP-14, matrix metalloproteinase
- MSCs, mesenchymal stem cells
- Matrix metalloproteinase-14
- Mesenchymal stem cells
- Wnt/β-catenin signal inhibitor
- chronic liver injury
- hBM-MNCs, human bone marrow mononuclear cells
- iPS cells, induced pluripotent stem cells
- αSMA, α-smooth muscle actin
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Affiliation(s)
- Kenji Fukushima
- Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Noriko Itaba
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yohei Kono
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Shizuma Okazaki
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Shinpei Enokida
- Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan
| | - Naomi Kuranobu
- Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Makoto Enokida
- Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan
| | - Hideki Nagashima
- Division of Orthopedic Surgery, Department of Sensory and Motor Organs, School of Medicine, Faculty of Medicine, Tottori University, Yonago, 683-8504, Japan
| | - Susumu Kanzaki
- Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan
- Asahigawaso Rehabilitation & Medical Center, Okayama, 703-8555, Japan
| | - Noriyuki Namba
- Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Goshi Shiota
- Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
- Corresponding author. Division of Medical Genetics and Regenerative Medicine, Department of Genomic Medicine and Regenerative Therapy, School of Medicine, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan. Fax: +81-859-38-6430.
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Hennes DMZB, Rosamilia A, Werkmeister JA, Gargett CE, Mukherjee S. Endometrial SUSD2 + Mesenchymal Stem/Stromal Cells in Tissue Engineering: Advances in Novel Cellular Constructs for Pelvic Organ Prolapse. J Pers Med 2021; 11:jpm11090840. [PMID: 34575617 PMCID: PMC8471527 DOI: 10.3390/jpm11090840] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/19/2021] [Accepted: 08/21/2021] [Indexed: 12/15/2022] Open
Abstract
Cellular therapy is an emerging field in clinical and personalised medicine. Many adult mesenchymal stem/progenitor cells (MSC) or pluripotent derivatives are being assessed simultaneously in preclinical trials for their potential treatment applications in chronic and degenerative human diseases. Endometrial mesenchymal stem/progenitor cells (eMSC) have been identified as clonogenic cells that exist in unique perivascular niches within the uterine endometrium. Compared with MSC isolated from other tissue sources, such as bone marrow and adipose tissue, eMSC can be extracted through less invasive methods of tissue sampling, and they exhibit improvements in potency, proliferative capacity, and control of culture-induced differentiation. In this review, we summarize the potential cell therapy and tissue engineering applications of eMSC in pelvic organ prolapse (POP), emphasising their ability to exert angiogenic and strong immunomodulatory responses that improve tissue integration of novel surgical constructs for POP and promote vaginal tissue healing.
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Affiliation(s)
- David M. Z. B. Hennes
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (A.R.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia
- Pelvic Floor Disorders Unit, Monash Health, Clayton, VIC 3168, Australia
- Correspondence: (D.M.Z.B.H.); (S.M.)
| | - Anna Rosamilia
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (A.R.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia
- Pelvic Floor Disorders Unit, Monash Health, Clayton, VIC 3168, Australia
| | - Jerome A. Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (A.R.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (A.R.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia
| | - Shayanti Mukherjee
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (A.R.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia
- Correspondence: (D.M.Z.B.H.); (S.M.)
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Kuca-Warnawin E, Janicka I, Szczęsny P, Olesińska M, Bonek K, Głuszko P, Kontny E. Modulation of T-Cell Activation Markers Expression by the Adipose Tissue-Derived Mesenchymal Stem Cells of Patients with Rheumatic Diseases. Cell Transplant 2021; 29:963689720945682. [PMID: 32878464 PMCID: PMC7784571 DOI: 10.1177/0963689720945682] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Activated T lymphocytes play an important role in the pathogenesis of rheumatic diseases (RD). Mesenchymal stem cells (MSCs) possess immunoregulatory activities but such functions of MSCs from bone marrow of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and ankylosing spondylitis (AS) patients are impaired. Adipose tissue–derived MSCs (ASCs) are an optional pool of therapeutically useful MSCs, but biology of these cells in RD is poorly known. This study aimed at investigating the effect of ASCs from RD patients and healthy donors (HD) on the expression of the key T-cell activation markers. Methods: ASCs were isolated from subcutaneous abdominal fat from SLE (n = 16), SSc (n = 18), and AS (n = 16) patients, while five human ASCs lines from HD were used as a control. Untreated and cytokine (tumor necrosis factor α + interferon γ)-treated ASCs were co-cultured with allogenic, mitogen (phytohemagglutinin)-stimulated peripheral blood mononuclear cells (PBMCs) or purified anti-CD3/CD28-activated CD4+ T lymphocytes. Contacting and noncontacting ASCs-PBMCs co-cultures were performed. RD/ASCs were analyzed in co-cultures with both allogeneic and autologous PBMCs. Flow cytometry analysis was used to evaluate expression of CD25, HLA-DR, and CD69 molecules on CD4+ and CD8+ cells. Results: In co-cultures with allogeneic, activated CD4+ T cells and PBMCs, HD/ASCs and RD/ASCs downregulated CD25 and HLA-DR, while upregulated CD69 molecules expression on both CD4+ and CD8+ cells with comparable potency. This modulatory effect was similar in contacting and noncontacting co-cultures. RD/ASCs exerted weaker inhibitory effect on CD25 expression on autologous than allogeneic CD4+ and CD8+ T cells. Conclusion: RD/ASCs retain normal capability to regulate expression of activation markers on allogeneic T cells. Both HD/ASCs and RD/ASCs exert this effect independently of their activation status, mostly through the indirect pathway and soluble factors. However, autologous CD4+ and CD8+ T cells are partially resistant to RD/ASCs inhibition of CD25 expression, suggesting weaker control of T-cell activation in vivo.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Iwona Janicka
- Department of Pathophysiology and Immunology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Piotr Szczęsny
- Clinic of Connective Tissue Diseases, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Marzena Olesińska
- Clinic of Connective Tissue Diseases, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Krzysztof Bonek
- Department of Rheumatology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Piotr Głuszko
- Department of Rheumatology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
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Fu J, Wang Y, Jiang Y, Du J, Xu J, Liu Y. Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:377. [PMID: 34215342 PMCID: PMC8254211 DOI: 10.1186/s13287-021-02456-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/12/2021] [Indexed: 12/30/2022] Open
Abstract
Objectives Over the past decades, many studies focused on mesenchymal stem cells (MSCs) therapy for bone regeneration. Due to the efficiency of topical application has been widely dicussed and systemic application was also a feasible way for new bone formation, the aim of this study was to systematically review systemic therapy of MSCs for bone regeneration in pre-clinical studies. Methods The article search was conducted in PubMed and Embase databases. Original research articles that assessed potential effect of systemic application of MSCs for bone regeneration in vivo were selected and evaluated in this review, according to eligibility criteria. The efficacy of MSC systemic treatment was analyzed by random effects meta-analysis, and the outcomes were expressed in standard mean difference (SMD) and its 95% confidence interval. Subgroup analyses were conducted on animal species and gender, MSCs types, frequency and time of injection, and bone diseases. Results Twenty-three articles were selected in this review, of which 21 were included in meta-analysis. The results showed that systemic therapy increased bone mineral density (SMD 3.02 [1.84, 4.20]), bone volume to tissue volume ratio (2.10 [1.16, 3.03]), and the percentage of new bone area (7.03 [2.10, 11.96]). Bone loss caused by systemic disease tended to produce a better response to systemic treatment (p=0.05 in BMD, p=0.03 in BV/TV). Conclusion This study concluded that systemic therapy of MSCs promotes bone regeneration in preclinical experiments. These results provided important information for the systemic application of MSCs as a potential application of bone formation in further animal experiments. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02456-w.
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Affiliation(s)
- Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yanxue Wang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yiyang Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
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Xie Y, Liu S, Wang L, Yang H, Tai C, Ling L, Chen L, Liu S, Wang B. Individual heterogeneity screened umbilical cord-derived mesenchymal stromal cells with high Treg promotion demonstrate improved recovery of mouse liver fibrosis. Stem Cell Res Ther 2021; 12:359. [PMID: 34158112 PMCID: PMC8220795 DOI: 10.1186/s13287-021-02430-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 06/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background To investigate the heterogeneities of human umbilical cord mesenchymal stromal cells (HUCMSCs) derived from different donors and their therapeutic variations when applied to mouse liver fibrosis model. Methods The characteristics of HUCMSCs derived from multiple donors were comprehensively analyzed including expressions of surface markers, viability, growth curve, karyotype analysis, tumorigenicity, differentiation potentials, and immune regulation capability. Then, the HUCMSCs with distinct immunomodulatory effects were applied to treat mouse liver fibrosis and their therapeutic effects were observed. Results The HUCMSCs derived from multiple donors kept a high consistency in surface marker expressions, viability, growth curve, and tumorigenicity in nude mice but had robust heterogeneities in differentiation potentials and immune regulations. In addition, three HUCMSC lines applied to mice liver fibrosis model had different therapeutic outcomes, in line with individual immune regulation capability. Conclusion The HUCMSCs derived from different donors have individual heterogeneity, which potentially lead to distinct therapeutic outcomes in mouse liver fibrosis, indicating we could make use of the donor-variation of MSCs to screen out guaranteed general indicators of MSCs for specific diseases in further stromal cell therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02430-6.
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Affiliation(s)
- Yuanyuan Xie
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Shuo Liu
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Liudi Wang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Hui Yang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Chenxu Tai
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Li Ling
- Department of Endocrinology, University Health Science Center, Hua Zhong University of Science and Technology Union Shenzhen Hospital and The 6th Affiliated Hospital of Shenzhen, Shenzhen, 518052, Guangdong, People's Republic of China
| | - Libo Chen
- Department of Endocrinology, University Health Science Center, Hua Zhong University of Science and Technology Union Shenzhen Hospital and The 6th Affiliated Hospital of Shenzhen, Shenzhen, 518052, Guangdong, People's Republic of China
| | - Shanshan Liu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China.
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Neurogenic and Neuroprotective Potential of Stem/Stromal Cells Derived from Adipose Tissue. Cells 2021; 10:cells10061475. [PMID: 34208414 PMCID: PMC8231154 DOI: 10.3390/cells10061475] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 01/01/2023] Open
Abstract
Currently, the number of stem-cell based experimental therapies in neurological injuries and neurodegenerative disorders has been massively increasing. Despite the fact that we still have not obtained strong evidence of mesenchymal stem/stromal cells’ neurogenic effectiveness in vivo, research may need to focus on more appropriate sources that result in more therapeutically promising cell populations. In this study, we used dedifferentiated fat cells (DFAT) that are proven to demonstrate more pluripotent abilities in comparison with standard adipose stromal cells (ASCs). We used the ceiling culture method to establish DFAT cells and to optimize culture conditions with the use of a physioxic environment (5% O2). We also performed neural differentiation tests and assessed the neurogenic and neuroprotective capability of both DFAT cells and ASCs. Our results show that DFAT cells may have a better ability to differentiate into oligodendrocytes, astrocytes, and neuron-like cells, both in culture supplemented with N21 and in co-culture with oxygen–glucose-deprived (OGD) hippocampal organotypic slice culture (OHC) in comparison with ASCs. Results also show that DFAT cells have a different secretory profile than ASCs after contact with injured tissue. In conclusion, DFAT cells constitute a distinct subpopulation and may be an alternative source in cell therapy for the treatment of nervous system disorders.
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IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22115772. [PMID: 34071285 PMCID: PMC8198434 DOI: 10.3390/ijms22115772] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/23/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Tonsil-derived mesenchymal stem cells (T-MSCs) were reported to have suppressive effect on T cells, yet much remains unknown about the underlying mechanisms supporting this effect. We investigated the underlying mechanism of the immunomodulatory effect of T-MSCs on immune cell proliferation and cytokine production. Methods: We isolated T-MSCs from human palatine tonsil and evaluated the immunomodulatory capacity using RT-PCR, ELISA, and flow cytometry. Additionally, we assessed the expression of various soluble factors and several costimulatory molecules to detect the priming effect on T-MSCs. Results: T-MSCs significantly inhibited the immune cell proliferation and cytokine expression (TNF-α and IFN-γ) in the direct co-culture, but there was no suppressive effect in indirect co-culture. Additionally, we detected a remarkably higher expression of indoleamine 2,3-dioxygenase (IDO) in the primed T-MSCs having co-expression CD40. Moreover, immune cells or CD4+ T cells showed lower TNF-α, IFN-γ, and IL-4 expression when the primed T-MSC were added; whereas those findings were reversed when the inhibitor for IDO (not IL-4) or CD40 were added. Furthermore, T-bet and GATA3 levels were significantly decreased in the co-cultures of the primed T-MSCs and CD4+ T cells; whereas those findings were reversed when we added the neutralizing anti-CD40 antibody. Conclusions: Primed T-MSCs expressing IDO and CD40 may have immunomodulatory capacity via Th1-mediated and Th2-mediated immune response.
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Mendt M, Daher M, Basar R, Shanley M, Kumar B, Wei Inng FL, Acharya S, Shaim H, Fowlkes N, Tran JP, Gokdemir E, Uprety N, Nunez-Cortes AK, Ensley E, Mai T, Kerbauy LN, Melo-Garcia L, Lin P, Shen Y, Mohanty V, Lu J, Li S, Nandivada V, Wang J, Banerjee P, Reyes-Silva F, Liu E, Ang S, Gilbert A, Li Y, Wan X, Gu J, Zhao M, Baran N, Muniz-Feliciano L, Wilson J, Kaur I, Gagea M, Konopleva M, Marin D, Tang G, Chen K, Champlin R, Rezvani K, Shpall EJ. Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD. Front Immunol 2021; 12:631353. [PMID: 34017325 PMCID: PMC8130860 DOI: 10.3389/fimmu.2021.631353] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/24/2021] [Indexed: 12/26/2022] Open
Abstract
Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.
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Affiliation(s)
- Mayela Mendt
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rafet Basar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mayra Shanley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Bijender Kumar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Francesca Lim Wei Inng
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sunil Acharya
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hila Shaim
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalie Fowlkes
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jamie P Tran
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elif Gokdemir
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nadima Uprety
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ana K Nunez-Cortes
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Emily Ensley
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Thao Mai
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Lucila N Kerbauy
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, São Paulo, Brazil.,Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo, São Paulo, Brazil
| | - Luciana Melo-Garcia
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Paul Lin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yifei Shen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - JunJun Lu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sufang Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vandana Nandivada
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Pinaki Banerjee
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Francia Reyes-Silva
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Enli Liu
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sonny Ang
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - April Gilbert
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Xinhai Wan
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jun Gu
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ming Zhao
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalia Baran
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Luis Muniz-Feliciano
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jeffrey Wilson
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Indreshpal Kaur
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mihai Gagea
- Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - David Marin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Guilin Tang
- Clinical Cytogenetics Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Richard Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Planat-Benard V, Varin A, Casteilla L. MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism. Front Immunol 2021; 12:626755. [PMID: 33995350 PMCID: PMC8120150 DOI: 10.3389/fimmu.2021.626755] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials (immunomodulatory, anti-bacterial, anti-inflammatory, anti-oxidant defenses and metabolic adaptation…) and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation.
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Affiliation(s)
- Valerie Planat-Benard
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Audrey Varin
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Louis Casteilla
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
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Zhang T, Huang T, Su Y, Gao J. Mesenchymal Stem Cells‐Based Targeting Delivery System: Therapeutic Promises and Immunomodulation against Tumor. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Tianyuan Zhang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Ting Huang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Yuanqin Su
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Jianqing Gao
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Cancer Center of Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
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Liu F, Chen H, Chen T, Lau CS, Yu FX, Chen K, Chen HP, Pan RS, Chan GCF, Zhang XY, Nie YJ. Immunotherapeutic effects of allogeneic mesenchymal stem cells on systemic lupus erythematosus. Lupus 2021; 29:872-883. [PMID: 32580680 DOI: 10.1177/0961203320928419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Mesenchymal stem cells have been applied to treat graft versus host disease as they have immunosuppressive ability and can overcome the major histocompatibility complex-histocompatibility barrier. The potential of allogeneic mesenchymal stem cells in treating systemic lupus erythematosus (SLE) was investigated in this study. MRL/lpr mice which can develop acquired SLE-like phenotypes were selected as an animal model. Mesenchymal stem cells obtained from green fluorescent protein-transgenic ICR mice were infused into MRL/lpr mice at either the early or late stage of disease. The dosage was 1 × 106/mice per infusion. Mice were stratified into six groups including negative controls and those receiving one, two, three, four or five doses at 2-weekly intervals. The phenotypes were monitored regularly. After treatment, the spleen CD3+CD4-CD8- T and CD19+ B cells of two-dose mesenchymal stem cell-treated mice were significantly lower than those of the phosphate-buffered saline control. In terms of reducing the severity of SLE such as hair loss, skin ulcers, proteinuria and anti-dsDNA level, mesenchymal stem cells given at the early stage responded better and mice receiving two doses of mesenchymal stem cells performed better than those receiving either a lower dose (one dose) or higher doses (three, four or five doses). In conclusion, early treatment and an optimal dose of mesenchymal stem cells can effectively suppress the murine SLE model.
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Affiliation(s)
- Fang Liu
- The Medical College, Guizhou University, Guiyang, China
| | - Hui Chen
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Tao Chen
- Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Chak-Sing Lau
- Department of Medicine, The University of Hong Kong, Pokfulam, China
| | - Fu-Xun Yu
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Kun Chen
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Hou-Ping Chen
- Department of Orthopedics, Guiyang Children's Hospital, Guiyang, China
| | - Run-Sang Pan
- Department of Orthopedics, Guiyang Children's Hospital, Guiyang, China
| | - Godfrey Chi-Fung Chan
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiang-Yan Zhang
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Ying-Jie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
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Ouyang L, Cao J, Dai Q, Qiu D. New insight of immuno-engineering in osteoimmunomodulation for bone regeneration. Regen Ther 2021; 18:24-29. [PMID: 33778136 PMCID: PMC7985270 DOI: 10.1016/j.reth.2021.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
With the continuous development of bone tissue engineering, the importance of immune response in bone tissue regeneration is gradually recognized. The new bone tissue engineering products should possess immunoregulatory functions, harmonizing the interactions between the bone's immune defense and regeneration systems, and promoting tissue regeneration. This article will interpret the relationship between the bone immune system, bone tissue regeneration, as well as the immunoregulatory function of bone biomaterials and seed stem cells in bone tissue engineering. This review locates arears for foucusing efforts at providing novel designs ideas about the development of immune-mediation targeted bone tissue engineering products and the evaluation strategy for the osteoimmunomodulation property of bone biomaterials.
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Affiliation(s)
- Long Ouyang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiankun Cao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Dai
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Daojing Qiu
- Department of Orthopedics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Zheng S, Huang K, Xia W, Shi J, Liu Q, Zhang X, Li G, Chen J, Wang T, Chen X, Xiang AP. Mesenchymal Stromal Cells Rapidly Suppress TCR Signaling-Mediated Cytokine Transcription in Activated T Cells Through the ICAM-1/CD43 Interaction. Front Immunol 2021; 12:609544. [PMID: 33692786 PMCID: PMC7937648 DOI: 10.3389/fimmu.2021.609544] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 02/01/2021] [Indexed: 12/15/2022] Open
Abstract
Cell-cell contact participates in the process of mesenchymal stromal cell (MSC)-mediated T cell modulation and thus contributes to MSC-based therapies for various inflammatory diseases, especially T cell-mediated diseases. However, the mechanisms underlying the adhesion interactions between MSCs and T cells are still poorly understood. In this study, we explored the interaction between MSCs and T cells and found that activated T cells could rapidly adhere to MSCs, leading to significant reduction of TNF-α and IFN-γ mRNA expression. Furthermore, TCR-proximal signaling in activated T cells was also dramatically suppressed in the MSC co-culture, resulting in weakened Ca2+ signaling. MSCs rapidly suppressed TCR signaling and its downstream signaling in a cell-cell contact-dependent manner, partially through the ICAM-1/CD43 adhesion interaction. Blockade of either ICAM-1 on MSCs or CD43 on T cells significantly reversed this rapid suppression of proinflammatory cytokine expression in T cells. Mechanistically, MSC-derived ICAM-1 likely disrupts CD43-mediated TCR microcluster formation to limit T cell activation. Taken together, our results reveal a fast mechanism of activated T cell inhibition by MSCs, which provides new clues to unravel the MSC-mediated immunoregulatory mechanism for aGVHD and other severe acute T cell-related diseases.
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Affiliation(s)
- Shuwei Zheng
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Ke Huang
- Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenjie Xia
- Guangzhou Blood Centre, Institute of Blood Transfusion, Guangzhou, China
| | - Jiahao Shi
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoran Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Gang Li
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jieying Chen
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Tao Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyong Chen
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China.,Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Andy Peng Xiang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
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Andia I, Maffulli N. Mesenchymal stromal cell products for intra-articular knee injections for conservative management of osteoarthritis. Ther Adv Musculoskelet Dis 2021; 13:1759720X21996953. [PMID: 33680097 PMCID: PMC7897835 DOI: 10.1177/1759720x21996953] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Sports injuries and secondary joint problems, mainly of the knee, are common, especially in sports associated with high impact activities and/or torsional loading. The consequences can be career ending in elite athletes and reduce exercise activities in recreational people. Various cell products can be injected intra-articularly. First, fresh cellular mixtures can be prepared and injected in the same day, such as stromal vascular fraction of adipose tissue (SVF) and bone marrow concentrates (BMCs). Second, autologous mesenchymal stromal cells (MSCs) can be isolated from BMCs or SVF and, after several weeks of laboratory expansion, several millions of MSCs can be obtained for intra-articular injection. Finally, allogeneic MSCs from the bone marrow, adipose tissue or perinatal tissues of selected donors constitute an ‘off-the-shelf’ experimental treatment for injection delivery in patients with osteoarthritis of the knee. The perceived efficacy of all these products is based on the hypothesis of a paracrine mechanism of action: when living cells are delivered within the joint, they establish a molecular cross-talk with immune cells and local cell phenotypes, thereby modulating inflammation with subsequent modifications in the catabolic/degenerative milieu. Current clinical research examines whether injection delivery of MSCs translates into actual clinical benefits. Overall, clinical studies lack the quality needed to answer major research questions, including clinical and structural efficacy, optimal cell dose, and number of injections and specific protocol for cell delivery. Poor experimental designs are exacerbated by the diversity of patient phenotypes that hinder comparisons between treatments. Further understanding of disease pathology is paramount to develop potent function assays and understand whether the host tissue, the cell product or both should be primed before MSCs are injected intra-articularly.
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Affiliation(s)
- Isabel Andia
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4DG, UK
| | - Nicola Maffulli
- Regenerative Therapies, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Bizkaia, Spain
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Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis. Stem Cell Res Ther 2021; 12:50. [PMID: 33422134 PMCID: PMC7796621 DOI: 10.1186/s13287-020-02118-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/22/2020] [Indexed: 12/19/2022] Open
Abstract
Background Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored. Methods The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression. Results hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR). Conclusion Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02118-3.
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Lu S, Qiao X. Single-cell profiles of human bone marrow-derived mesenchymal stromal cells after IFN-γ and TNF-α licensing. Gene 2020; 771:145347. [PMID: 33333228 DOI: 10.1016/j.gene.2020.145347] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/12/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pre-licensing mesenchymal stromal cells (MSCs) with IFN-γ and TNF-α can empower their immune fate and induce a more effective immune regulation. However, the cellular heterogeneity of MSCs limits our understanding of this inflammatory licensing. METHODS The publicly available Gene Expression Omnibus single-cell RNA sequencing (scRNA-seq) data of human bone marrow-derived MSCs with or without IFN-γ and TNF-α licensing were analyzed. Based on the scRNA-seq data and related marker genes, the cell-cycle, stemness, differentiative potencies, and immunomodulate capability of unlicensed and licensed MSCs were compared. RESULTS After removing low-quality cells and regressing out the ribosomal gene effects, high-quality data reflecting IFN-γ and TNF-α effect on MSCs were chosen for further analysis. Despite the heterogeneity, pre-licensing didn't influence the cell-cycle and stemness of human bone marrow-derived MSCs. The osteogenesis potencies were decreased, the chondrogenesis potencies were increased while the adipogenesis potencies were stable in licensed MSCs. Licensed MSCs also showed more effective immunomodulate capability including expression of related chemokines, cytokines, surface molecules, and receptors. CONCLUSION Collectively, our study showed the expression profiles of human bone marrow-derived unlicensed and licensed MSCs about the cell cycle, stemness, differentiative potencies, and immunomodulate capability at single-cell resolution, which may help the comprehensive understanding about the inflammatory licensing of human bone marrow-derived MSCs and their further clinical application.
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Affiliation(s)
- Shuanglong Lu
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China
| | - Xiaohong Qiao
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China.
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Li Y, Ma K, Zhang L, Xu H, Zhang N. Human Umbilical Cord Blood Derived-Mesenchymal Stem Cells Alleviate Dextran Sulfate Sodium-Induced Colitis by Increasing Regulatory T Cells in Mice. Front Cell Dev Biol 2020; 8:604021. [PMID: 33330503 PMCID: PMC7732515 DOI: 10.3389/fcell.2020.604021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD), which main clinical manifestations include abdominal pain and diarrhea occurring repeatedly, is a kind of autoimmune disease. It has been reported in preceding studies that mesenchymal stem cells (MSCs) can reduce inflammation by regulating the function of immune cells. But studies about the interaction between MSCs and adaptive immune cells, especially in IBD models, are insufficient. Therefore, the objective of this research was to estimate the therapeutic effects of MSCs from human umbilical cord blood (hUCB-MSCs) in an IBD model of rodent and to clarify the therapeutic mechanisms of hUCB-MSCs. Dextran sulfate sodium (DSS) was used to induce colitis in rodent. Mice with colitis were treated with intraperitoneal infusions of hUCB-MSCs and evaluated for mortality and diverse disease symptoms containing weight reduction, diarrhea, and bloody stools. The levels of histopathologic severity and generation of regulatory T cells (Treg) were also determined. Treatment with hUCB-MSCs ameliorated the clinical and histopathologic severity of acute and chronic colitis in mice. Furthermore, T cell infiltration into the inflamed colon was significantly decreased (p = 0.0175), and Foxp3+ cells were substantially higher in the hUCB-MSC group than that of the DSS group. Our results suggest that hUCB-MSCs are able to alleviate inflammation via adding Foxp3+ Tregs in an IBD model of mouse. As a result, these findings suggest the opportunity of hUCB-MSC being applied to patients with IBD.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Ke Ma
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Luping Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Nan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Zhu J, Feng B, Xu Y, Chen W, Sheng X, Feng X, Shi X, Liu J, Pan Q, Yu J, Li L, Cao H. Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C + CD8 + T cells. Cell Death Dis 2020; 11:829. [PMID: 33024074 PMCID: PMC7538431 DOI: 10.1038/s41419-020-03036-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022]
Abstract
Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8+ T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce ALI in mice. ALI mice were treated with MSCs via intratracheal instillation. Survival rate, histopathological changes, protein levels, total cell count, cytokine levels, and chemokine levels in alveolar lavage fluid were used to determine the efficacy of MSCs. Mass cytometry and single-cell RNA sequencing (scRNA-seq) were used to characterize the CD8+ T cells in the lungs. Ly6C- CD8+ T cells are prevalent in normal mice, whereas a specialized effector phenotype expressing a high level of Ly6C is predominant in advanced disease. MSCs significantly mitigated ALI and improved survival. MSCs decreased the infiltration of CD8+ T cells, especially Ly6C+ CD8+ T cells into the lungs. Mass cytometry revealed that CD8+ T cells expressing high Ly6C and CXCR3 levels caused tissue damage in the lungs of ALI mice, which was alleviated by MSCs. The scRNA-seq showed that Ly6C+ CD8+ T cells exhibited a more activated phenotype and decreased expression of proinflammatory factors that were enriched the most in immune chemotaxis after treatment with MSCs. We showed that CD8+ T cells play an important role in MSC-mediated ALI remission, and both infiltration quantity and proinflammatory function were inhibited by MSCs, indicating a potential mechanism for therapeutic intervention.
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Affiliation(s)
- Jiaqi Zhu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Bing Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Yanping Xu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Xinyu Sheng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Xiaowei Shi
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Jingqi Liu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, 310003, China.
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Road, Hangzhou City, 310003, China.
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, 79 Qingchun Road, Hangzhou City, 310003, China.
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He X, Yang Y, Yao M, Yang L, Ao L, Hu X, Li Z, Wu X, Tan Y, Xing W, Guo W, Bellanti JA, Zheng SG, Xu X. Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis. Ann Rheum Dis 2020; 79:1298-1304. [PMID: 32561603 DOI: 10.1136/annrheumdis-2020-217798] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To clarify the key role of circulating interferon-γ (IFN-γ) and to improve the clinical efficacy of mesenchymal stem cell (MSC) transplantation (MSCT) in patients with rheumatoid arthritis (RA). METHODS Study of wild-type or IFN-γR-/- MSCT was first evaluated in a murine model of collagen-induced arthritis (CIA) following which a phase 1/2 randomised controlled study was conducted in 63 patients with RA who responded poorly to regular clinical treatments. Subjects were randomly assigned to an MSCT monotherapy group (n=32) or an MSCT plus recombinant human IFN-γ treatment group (n=31), with 1 year of follow-up. The primary end points consisted of efficacy as assessed as good or moderate EULAR response rates and the proportion of patients at 3 months attaining American College of Rheumatology 20 (ACR20) response rates. RESULTS In the murine studies, wild-type MSCT significantly improved the clinical severity of CIA, while IFN-γR-/- MSCT aggravated synovitis, and joint and cartilage damage. Transitioning from the murine to the clinical study, the 3-month follow-up results showed that the efficacy and ACR20 response rates were attained in 53.3% patients with MSCT monotherapy and in 93.3% patients with MSCT combined with IFN-γ treatment (p<0.05). No new or unexpected safety issues were encountered in 1-year follow-up for either treatment group. CONCLUSIONS The results of this study show that IFN-γ is a key factor in determining the efficacy of MSCT in the treatment of RA, and that an MSC plus IFN-γ combination therapeutic strategy can greatly improve the clinical efficacy of MSC-based therapy in RA patients.
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Affiliation(s)
- Xiao He
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
- PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Yi Yang
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Department of Rheumatology and Clinical Immunology, Daping Hospital, Army Military Medical University, Chongqing, China
| | - Mengwei Yao
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Lei Yang
- Force Health Team of 61365 Troops of the Chinese People's Liberation Army, Tianjin, China
| | - Luoquan Ao
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Xueting Hu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Xiaofeng Wu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Yan Tan
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
| | - Joseph A Bellanti
- Departments of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Song Guo Zheng
- Division of Rheumatology, Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Military Medical University,Chongqing, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
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Hume RD, Chong JJH. The Cardiac Injury Immune Response as a Target for Regenerative and Cellular Therapies. Clin Ther 2020; 42:1923-1943. [PMID: 33010930 DOI: 10.1016/j.clinthera.2020.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/20/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Despite modern reperfusion and pharmacologic therapies, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Therefore, the development of further therapeutics affecting post-MI recovery poses significant benefits. This review focuses on the post-MI immune response and immunomodulatory therapeutics that could improve the wound-healing response. METHODS This narrative review used OVID versions of MEDLINE and EMBASE searching for clinical therapeutics targeting the immune system during MI. Preclinical models and clinical trials were included. Additional studies were sourced from the reference lists of relevant articles and other personal files. FINDINGS After MI, cardiomyocytes are starved of oxygen and undergo cell death via coagulative necrosis. This process activates the immune system and a multifaceted wound-healing response, comprising a number of complex and overlapping phases. Overactivation or persistence of one or more of these phases can have potentially lethal implications. This review describes the immune response post-MI and any adverse events that can occur during these different phases. Second, we describe immunomodulatory therapies that attempt to target these immune cell aberrations by mitigating or diminishing their effects on the wound-healing response. Also discussed are adult stem/progenitor cell therapies, exosomes, and regulatory T cells, and their immunomodulatory effects in the post-MI setting. IMPLICATIONS An updated understanding into the importance of various inflammatory cell phenotypes, coupled with new technologies, may hold promise for a new era of immunomodulatory therapeutics. The implications of such therapies could dramatically improve patients' quality of life post-MI and reduce the incidence of progressive heart failure.
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Affiliation(s)
- Robert D Hume
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW 2145, Australia
| | - James J H Chong
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW 2145, Australia; Department of Cardiology, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia.
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Paul K, Darzi S, Werkmeister JA, Gargett CE, Mukherjee S. Emerging Nano/Micro-Structured Degradable Polymeric Meshes for Pelvic Floor Reconstruction. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E1120. [PMID: 32517067 PMCID: PMC7353440 DOI: 10.3390/nano10061120] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
Abstract
Pelvic organ prolapse (POP) is a hidden women's health disorder that impacts 1 in 4 women across all age groups. Surgical intervention has been the only treatment option, often involving non-degradable meshes, with variable results. However, recent reports have highlighted the adverse effects of meshes in the long term, which involve unacceptable rates of erosion, chronic infection and severe pain related to mesh shrinkage. Therefore, there is an urgent unmet need to fabricate of new class of biocompatible meshes for the treatment of POP. This review focuses on the causes for the downfall of commercial meshes, and discusses the use of emerging technologies such as electrospinning and 3D printing to design new meshes. Furthermore, we discuss the impact and advantage of nano-/microstructured alternative meshes over commercial meshes with respect to their tissue integration performance. Considering the key challenges of current meshes, we discuss the potential of cell-based tissue engineering strategies to augment the new class of meshes to improve biocompatibility and immunomodulation. Finally, this review highlights the future direction in designing the new class of mesh to overcome the hurdles of foreign body rejection faced by the traditional meshes, in order to have safe and effective treatment for women in the long term.
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Affiliation(s)
- Kallyanashis Paul
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (K.P.); (S.D.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Saeedeh Darzi
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (K.P.); (S.D.); (J.A.W.); (C.E.G.)
| | - Jerome A. Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (K.P.); (S.D.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (K.P.); (S.D.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
| | - Shayanti Mukherjee
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton 3168, Australia; (K.P.); (S.D.); (J.A.W.); (C.E.G.)
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Australia
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48
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Wang S, Wang G, Zhang L, Li F, Liu K, Wang Y, Shi Y, Cao K. Interleukin-17 promotes nitric oxide-dependent expression of PD-L1 in mesenchymal stem cells. Cell Biosci 2020; 10:73. [PMID: 32509271 PMCID: PMC7249370 DOI: 10.1186/s13578-020-00431-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Background Interleukin-17A (IL-17) is an evolutionary conserved cytokine and best known for its role in boosting immune response. However, recent clinical researches showed that abundant IL-17 in tumor microenvironment was often associated with poor prognosis and reduced cytotoxic T cell infiltration. These contradictory phenomena suggest that IL-17 may have unique target cells in tumor microenvironment which switch its biological consequences from pro-inflammatory to anti-inflammatory. Mesenchymal stem/stromal cells (MSCs) are a major component of the tumor microenvironment. Upon cytokine stimulation, MSCs can express a plenary of inhibitory molecules, playing a critical role in tumor development and progression. Therefore, we aim to investigate the role of IL-17 in MSC-mediated immunosuppression. Results We found IFNγ and TNFα, two major cytokines in tumor microenvironment, could induce programmed death-ligand 1 (PD-L1) expression in MSCs. Interestingly, IL-17 has a synergistic effect with IFNγ and TNFα in elevating PD-L1 expression in MSCs. The presence of IL-17 empowered MSCs with strong immunosuppression abilities and enabled MSCs to promote tumor progression in a PD-L1 dependent manner. The upregulated PD-L1 expression in MSCs was due to the accumulation of nitric oxide (NO). On one hand, NO donor could mimic the effects of IL-17 on MSCs; on the other hand, IL-17 failed to enhance PD-L1 expression in inducible nitric oxide synthase (iNOS) deficient MSCs or with iNOS inhibitor presence. Conclusions Our study demonstrates that IL-17 can significantly increase the expression of PD-L1 by MSCs through iNOS induction. This IL-17-MSCs-PD-L1 axis shapes the immunosuppressive tumor microenvironment and facilitates tumor progression.
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Affiliation(s)
- Shijia Wang
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Academy of Sciences (CAS), Shanghai, 200031 China
| | - Guan Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Liying Zhang
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123 China
| | - Fengying Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Keli Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Yufang Shi
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Academy of Sciences (CAS), Shanghai, 200031 China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.,The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123 China
| | - Kai Cao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
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The voltage-gated proton channel hHv1 is functionally expressed in human chorion-derived mesenchymal stem cells. Sci Rep 2020; 10:7100. [PMID: 32346069 PMCID: PMC7188850 DOI: 10.1038/s41598-020-63517-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 04/01/2020] [Indexed: 01/08/2023] Open
Abstract
The voltage-gated proton channel Hv1 is widely expressed, among others, in immune and cancer cells, it provides an efficient cytosolic H+extrusion mechanism and regulates vital functions such as oxidative burst, migration and proliferation. Here we demonstrate the presence of human Hv1 (hHv1) in the placenta/chorion-derived mesenchymal stem cells (cMSCs) using RT-PCR. The voltage- and pH-dependent gating of the current is similar to that of hHv1 expressed in cell lines and that the current is blocked by 5-chloro-2-guanidinobenzimidazole (ClGBI) and activated by arachidonic acid (AA). Inhibition of hHv1 by ClGBI significantly decreases mineral matrix production of cMSCs induced by conditions mimicking physiological or pathological (inorganic phosphate, Pi) induction of osteogenesis. Wound healing assay and single cell motility analysis show that ClGBI significantly inhibits the migration of cMSCs. Thus, seminal functions of cMSCs are modulated by hHv1 which makes this channel as an attractive target for controlling advantages/disadvantages of MSCs therapy.
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50
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Wagner MJ, Khan M, Mohsin S. Healing the Broken Heart; The Immunomodulatory Effects of Stem Cell Therapy. Front Immunol 2020; 11:639. [PMID: 32328072 PMCID: PMC7160320 DOI: 10.3389/fimmu.2020.00639] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular Disease (CVD) is a leading cause of mortality within the United States. Current treatments being administered to patients who suffered a myocardial infarction (MI) have increased patient survival, but do not facilitate the replacement of damaged myocardium. Recent studies demonstrate that stem cell-based therapies promote myocardial repair; however, the poor engraftment of the transferred stem cell populations within the infarcted myocardium is a major limitation, regardless of the cell type. One explanation for poor cell retention is attributed to the harsh inflammatory response mounted following MI. The inflammatory response coupled to cardiac repair processes is divided into two distinct phases. The first phase is initiated during ischemic injury when necrosed myocardium releases Danger Associated Molecular Patterns (DAMPs) and chemokines/cytokines to induce the activation and recruitment of neutrophils and pro-inflammatory M1 macrophages (MΦs); in turn, facilitating necrotic tissue clearance. During the second phase, a shift from the M1 inflammatory functional phenotype to the M2 anti-inflammatory and pro-reparative functional phenotype, permits the resolution of inflammation and the establishment of tissue repair. T-regulatory cells (Tregs) are also influential in mediating the establishment of the pro-reparative phase by directly regulating M1 to M2 MΦ differentiation. Current studies suggest CD4+ T-lymphocyte populations become activated when presented with autoantigens released from the injured myocardium. The identity of the cardiac autoantigens or paracrine signaling molecules released from the ischemic tissue that directly mediate the phenotypic plasticity of T-lymphocyte populations in the post-MI heart are just beginning to be elucidated. Stem cells are enriched centers that contain a diverse paracrine secretome that can directly regulate responses within neighboring cell populations. Previous studies identify that stem cell mediated paracrine signaling can influence the phenotype and function of immune cell populations in vitro, but how stem cells directly mediate the inflammatory microenvironment of the ischemic heart is poorly characterized and is a topic of extensive investigation. In this review, we summarize the complex literature that details the inflammatory microenvironment of the ischemic heart and provide novel insights regarding how paracrine mediated signaling produced by stem cell-based therapies can regulate immune cell subsets to facilitate pro-reparative myocardial wound healing.
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Affiliation(s)
- Marcus J Wagner
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Sadia Mohsin
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
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